U.S. patent number 8,470,337 [Application Number 12/047,482] was granted by the patent office on 2013-06-25 for therapeutic treatments using botulinum neurotoxin.
This patent grant is currently assigned to Allergan, Inc.. The grantee listed for this patent is Mitchell F. Brin, Aubrey N. Manack. Invention is credited to Mitchell F. Brin, Aubrey N. Manack.
United States Patent |
8,470,337 |
Manack , et al. |
June 25, 2013 |
Therapeutic treatments using botulinum neurotoxin
Abstract
Methods for treating a coronary risk factor (such as
hypertension, diabetes, hyperlipidemia and obesity) and/or a
respiratory disorder (such as asthma, chronic obstructive pulmonary
disease and bronchitis) and/or arthritis by local administration of
a botulinum neurotoxin to at least one of a head, neck or shoulder
location (for example, by subdermal, subcutaneous or intramuscular
administration of the botulinum neurotoxin) of a patient with a
coronary risk factor, respiratory disorder or arthritis.
Inventors: |
Manack; Aubrey N. (Costa Mesa,
CA), Brin; Mitchell F. (Newport Beach, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Manack; Aubrey N.
Brin; Mitchell F. |
Costa Mesa
Newport Beach |
CA
CA |
US
US |
|
|
Assignee: |
Allergan, Inc. (Irvine,
CA)
|
Family
ID: |
41063284 |
Appl.
No.: |
12/047,482 |
Filed: |
March 13, 2008 |
Prior Publication Data
|
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|
|
Document
Identifier |
Publication Date |
|
US 20090232850 A1 |
Sep 17, 2009 |
|
Current U.S.
Class: |
424/247.1;
424/239.1; 514/16.8 |
Current CPC
Class: |
A61K
38/164 (20130101); A61P 11/00 (20180101); A61P
9/00 (20180101); A61P 19/02 (20180101); A61P
25/00 (20180101); A61K 38/4893 (20130101) |
Current International
Class: |
A61K
39/08 (20060101); A61K 38/00 (20060101); A61P
19/02 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 605 501 |
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Jul 1994 |
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EP |
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WO 95/17904 |
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Jul 1995 |
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WO |
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WO 2004/041303 |
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May 2004 |
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WO |
|
Other References
Callaway et al 2001 Seminars in Cutaneous Medicine and Surgery,
vol. 20 No. 2 pp. 127-136. cited by examiner .
By Denise Mann Reviewed by Louise Chang 2006 WebMD, LLC. "Botox May
Cut Knee Osteoarthritis Pain". cited by examiner .
"Arthritis Special Report 2007 Botox and Knee Osteoarthritis".
cited by examiner .
U.S. Appl. No. 12/436,730, filed May 6, 2009, Brooks. cited by
applicant .
Ahuja, Vanita; et al.: Head and Neck Manifestations of
Gastroesophageal Reflux Disease, American Family Physician, vol.
60, No. 3, Sep. 1, 1999. cited by applicant .
Albanese, A.; et al.: The Use of Botulinum Toxin on Smooth Muscles,
Eur J Neurol Nov. 1995;2(Supp 3):29-33. cited by applicant .
Aoki K., et al, Mechanisms of the Antinociceptive Effect of
Subcutaneous BOTOX .RTM.: Inhibition of Peripheral and Central
Nociceptive Processing, Cephalalgia Sep. 2003; 23(7):649. cited by
applicant .
Bigalke, H.; et al.: Botulinum A Neurotoxin Inhibits
Non-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons
in Culture, Brian Research 360;318-324:1985. cited by applicant
.
Bigalke, H.; et al.: Tetanus Toxin and Botulinum A Toxin Inhibit
Release and Uptake of Various Transmitters, as Studied with
Particulate Preparations From Rat Brain and Spinal Cord, Naunyn
Schmiedeberg's Arch Pharmacol 316;244-251:1981. cited by applicant
.
Binz T. et al.: The Complete Sequence of Botulinum Neurotoxin Type
A and Comparison with Other Clostridial Neurotoxins, J. Biological
Chemistry 265(16);9153-9158:1990. cited by applicant .
Boyd R.S., et al.: The Effect of Botulinum Neurotoxin-B on Insulin
Release From a .beta.-cell Line, Mov Disord, 10(3):376:1995,
Abstract 19. cited by applicant .
Boyd R.S. et al.: The Insulin Secreting .beta.-cell Line, HIT-15,
Contains SNAP-25 which is a Target for Botulinum Neurotoxin-A, Mov
Disord, 10(3):376:1995, Abstract 20. cited by applicant .
Bushara K., Botulinum Toxin and Rhinorrhea, Otolaryngol Head Neck
Surg 1996; 114(3):507. cited by applicant .
Coffield, Eds. Jankovic J. et al.: Therapy With Botulinum Toxin,
Marcel Dekker, Inc., (1994), Chapter 1. cited by applicant .
Dykstra, D.D., et al.: Treatment of Detrusor-Sphincter Dyssynergia
with Botulinum A Toxin: A Double Blind Study, Arch Phys Med Rehabil
Jan. 1990; 71:24-6. cited by applicant .
Eaker, E.Y., et al.: Untoward Effects of Esophageal Botulinum Toxin
Injection in the Treatment of Achalasia, Dig Dis Sci Apr.
1997;42(4):724-7. cited by applicant .
Friedenberg, Frank; et al.: The Use of Botulinum Toxin for the
Treatment of Gastrointestinal Motility Disorders. Digestive
Diseases and Sciences, vol. 49, No. 2 Feb. 2004. cited by applicant
.
Gonelle-Gispert, C., et al.: SNAP-25a and -25b Isoforms are Both
Expressed in Insulin-Secreting Cells and Can Function in Insulin
Secretion, Biochem J. 1;339 (pt 1):159-165:1999. cited by applicant
.
Gui D., et al.: Botulinum Toxin Injected in the Gastric Wall
Reduces Body Weight and Food Intake in Rats, Aliment Pharmacol Ther
Jun. 2000; 14(6):829-834. cited by applicant .
Gui D., et al.: Effects of Botulinum Toxin on Gastric Emptying and
Digestive Secretions. A Possible Tool for Correction of Obesity?,
Naunyn Schmiedebergs Arch Pharmacol Jun. 2002; 365(Suppl 2):R22.
cited by applicant .
Habermann E., et al.: Tetanus Toxin and Botulinum A and C
Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse
Brain, J. Neurochem 51(2); 522-527:1988. cited by applicant .
Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the
Release of [.sup.3H]Noradrenaline and [.sup.3H]GABA From Rat Brain
Homogenate, Experientia 44; 224-226:1988. cited by applicant .
Habermann, (.sup.125I-Labelled Neurotoxin From Clostridium
Botulinum A: Preparation, Binding to Synaptosomes and Ascent to the
Spinal Cord, Naunyn-Schmiedeberg's Arch. Pharmacol. 1974; 281,
47-56. cited by applicant .
Harrison's Principles of Internal Medicine (1998), Edited by
Anthony Fauci et al., 14.sup.th edition, Published by McGraw Hill.
cited by applicant .
Katsambas A., et al.: Cutaneous Diseases of the Foot: Unapproved
Treatments, Clin Dermatol Nov.-Dec. 2002;20(6):689-699. cited by
applicant .
Keir, James, Botulinum Toxin-Physiology and Applications in Head
and Neck Disorders, Neck & Head, Jun. 2005, pp. 525-535. cited
by applicant .
Khawaja, Hassan Abbas; et al.: Botox in Dermatology, International
Journal of Dermatology 2001, 40, 311-317). cited by applicant .
Kohl A., et al.: Comparison of the Effect of Botulinum Toxin A
(Botox .RTM.) with the Highly-Purified Neurotoxin (NT 201) in the
Extensor Digitorum Brevis Muscle Test, Mo. Disord. 2000; 15(Suppl
3): 165. cited by applicant .
Kondo T., et al.: Modification of the Action of Pentagastrin on
Acid Secretion by Botulinum Toxin, Experientia 1977;33:750-751.
cited by applicant .
Kumar R and Seeberger LC: Long-term Safety, Efficacy, and Dosing of
Botulinum Toxin Type B (Myobloc .RTM.) in Cervical Dystonia (CD)
and Other Movement Disorders. Mov Disord 2002;17(Suppl
5):S292-S293. cited by applicant .
Lacy, Brian E., et al., The Treatment of Diabetic Gastroparesis
with Botulinum Toxin Injection of the Pylorus, Diabetes Care, vol.
27, No. 10, Oct. 2004, pp. 2341-2347. cited by applicant .
Li Y, et al., Sensory and Motor Denervation Influences Epidermal
Thickness in Rat Foot Glabrous Skin, Exp Neurol 1997; 147:452-462
(see p. 459). cited by applicant .
Marjama-Lyons, J., et al.: Tremor-Predominant Parkinson's Disease,
Drugs & Aging 16(4);273-278:2000. cited by applicant .
Meyer K.E. et al.: A Comparative Systemic Toxicity Study of
Neurobloc in Adult Juvenile Cynomolgus Monkeys, Mov. Disord
15(Suppl 2);54;2000. cited by applicant .
Miller, Larry S., et al.: Treatment of Idiopathic Gastroparesis
with Injection of Botulinum Toxin into the Pyloric Sphincter
Muscle, The American Journal of Gastroenterology, vol. 97, No. 7,
2002, pp. 1653-1660. cited by applicant .
Moyer E. et al.: Botulinum Toxin Type B: Experimental and Clinical
Experience, Chapter 6, pp. 71-85 of "Therapy With Botulinum Toxin",
Edited by Jankovic, J. et al. (1994), Marcel Dekker, Inc. cited by
applicant .
Naumann M., et al.: Botulinum Toxin Type A in the Treatment of
Focal, Axillary and Palmar Hyperhidrosis and Other Hyperhidrotic
Conditions, European J. Neurology 6 (Supp 4): S111-S115: 1999.
cited by applicant .
Payne M., et al.: Botulinum Toxin as a Novel Treatment for Self
Mutilation in Lesch-Nyhan Syndrome, Ann Neurol Sep. 2002;52(3 Supp
1):S157). cited by applicant .
Pearce, L.B., Pharmacologic Characterization of Botulinum Toxin for
Basic Science and Medicine, Toxicon 35(9); 1373-1412 at 1393, Sep.
1997;35(9). cited by applicant .
Qureshi, Waqar: Gastrointestinal Uses of Botulinum Toxin, Journal
of Clincial Gastroenterol, 200;34(2): 126-128), Feb. 2002;34(2).
cited by applicant .
Ragona, R.M., et al.: Management of Parotid Sialocele with
Botulinum Toxin, The Laryngoscope 109:1344-1346:1999. cited by
applicant .
Rogers J., et al.: Injections of Botulinum Toxin A in Foot
Dystonia, Neurology Apr. 1993;43(4 Supp 2). cited by applicant
.
Rohrbach S., et al.: Botulinum Toxin Type A Induces Apoptosis in
Nasal Glands of Guinea Pigs, Ann Otol Rhinol Laryngol Nov.
2001;110(11):1045-1050. cited by applicant .
Rohrbach S., et al.: Minimally Invasive Application of Botulinum
Toxin Type a in Nasal Hypersecretion, J Oto-Rhino-Laryngol
Nov.-Dec. 2001; 63(6):382-384. cited by applicant .
Rossi S., et al.: Immunohistochemical Localization of SNAP-25
Protein in the Stomach of Rat, Naunyn Schmiedebergs Arch Pharmacol
2002;365(Suppl 2):R37. cited by applicant .
Sanchez-Prieto, J., et al.: Botulinum Toxin A Blocks Glutamate
Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.
Biochem 165;675-681:1987. cited by applicant .
Schantz E.J., et al.: Preparation and Characterization of Botulinum
Toxin Type A for Human Treatment (in Particular pp. 44-45), Chapter
3 of Janovic, J., et al, Therapy with Botulinum Toxin, Marcel
Dekker, Inc (1994). cited by applicant .
Schantz, E.J., et al.: Properties and Use of Botulinum Toxin and
Other Microbial Neurotoxins in Medicine, Microbiol Rev.
56;80-99:1992. cited by applicant .
Sevim, S., et al.: Botulinum Toxin--A Therapy for Palmar and
Plantar Hyperhidrosis Acta Neurol Belg Dec. 2002;102(4):167-170.
cited by applicant .
Singh, Critical Aspects of Bacterial/Protein Toxins, pp. 63-84
(Chapter 4) of Natural Toxins II, Edited by B.R. Singh et al.,
Plenum Press, New York (1996). cited by applicant .
Sloop, Richard R.; et al.: Reconstituted Botulinum Toxin Type A
Does Not Lose Potency in Humans If it is Refrozen or Refrigerated
for 2 Weeks Before use, Neurology, 48:249-253:1997. cited by
applicant .
Spierings, ELH; et al.: Reflux-Triggered Migrained Headache
Originating from the Upper Gum/Teeth Cephalalgia, 2002, 22, p.
555-556). cited by applicant .
Suputtitada, A., Local Botulinum Toxin Type A Injections in the
Treatment of Spastic Toes, Am J Phys Med Rehabil Oct.
2002;81(10):770-775). cited by applicant .
Tacks, L., et al.: Idiopathic Toe Walking: Treatment with Botulinum
Toxin A Injection, Dev Med Child Neurol 2002;44(Suppl 91):6). cited
by applicant .
Thumshirn et al (Schweiz Rundsch Med Prax., Oct. 16,
2002;91(42):1741-7). cited by applicant .
Wang Z., et al.: Effects of Botulinum Toxin on Gastric Myoeletrical
and Vagal Activities in Dogs, Gastroenterology Apr. 2001;120(5
Suppl 1):A-718. cited by applicant .
Weigand et al.: .sup.125I-labelled Botulinum A
Neurotoxin:Pharmacokinetics in Cats After Intramuscular Injection,
Nauny-Schmiedeberg's Arch. Pharmacol. 1976;292, 161-165. cited by
applicant .
Wiesel P.H. et al.: Botulinum Toxin for Refractory Postoperative
Pyloric Spasm, Endoscopy 1997;29(2):132. cited by applicant .
Zhao, Xiaotuan, et al.: Botulinum Toxin for Spastic Gi Disorders: A
Systematic Review, Gastrointestinal Endoscopy, vol. 57, No. 2,
2003, pp. 219-235. cited by applicant.
|
Primary Examiner: Ford; Vanessa L
Assistant Examiner: Archie; Nina
Attorney, Agent or Firm: Chan; Ted Phan; Brigitte Condino;
Debra
Claims
What is claimed is:
1. A method for treating osteoarthritis pain in a patient in need
thereof, the method comprising the step of intramuscular
administration of a therapeutically effective amount of botulinum
toxin bilaterally to the splenius capitis and temporalis muscles of
a patient suffering osteoarthritis pain, thereby decreasing the
osteroarthritis pain.
2. The method of claim 1 wherein the botulinum neurotoxin is
botulinum neurotoxin type A.
3. The method of claim 1, wherein the osteoarthritis pain
experienced by the patient is experienced in a knee joint.
4. The method of claim 1, wherein the patient has no improvement
with an oral medication.
5. The method of claim 4, wherein the oral medication is a non
steroidal anti-inflammatory drug, COX-2 inhibitor, analgesics or a
corticosteroid.
6. The method of claim 1, wherein the botulinum toxin administered
is from about 5 units to about 2500 units of a botulinum toxin type
A or from about 100 to about 25,000 units of a botulinum toxin type
B.
Description
BACKGROUND
The present invention relates to therapeutic methods utilizing a
botulinum neurotoxin such as for treating cardiac risk factors
(e.g. hypertension, diabetes, hyperlipidemia, and obesity) and/or
respiratory disorders (e.g. asthma, bronchitis and chronic
obstructive pulmonary disease (COPD)) and/or arthritis. More
particularly, the present invention relates to methods for treating
various cardiac risk factors and/or respiratory disorders and/or
arthritis utilizing local administration of at least one botulinum
neurotoxin.
Coronary Risk Factors
A coronary (or cardiac) risk factor is a condition and/or behavior
that increases a patient's chances of developing a coronary heart
disease. A coronary heart disease is also called coronary artery
disease (CAD), ischaemic heart disease or atherosclerotic heart
disease and is the end result of the accumulation of atheromatous
plaques in walls of the arteries that supply heart muscle with
oxygen and nutrients. The fewer total number of risk factors that a
patient has, the less risk the patient has of developing a coronary
heart disease. Additionally, the greater the level of a particular
risk factor (i.e. a clinically measurable aspect of the risk
factor, for example having a total blood cholesterol level of 200
mg/dL or greater rather than below 200 mg/dL), the greater is the
risk that the patient will develop a coronary heart disease.
Some coronary risk factors cannot be controlled. Examples of
uncontrollable coronary risk factors include, for example, age and
genetic disposition. The risk of developing some coronary heart
disease simply increases with every passing year. For example men
ages 45 and older and women ages 55 and older are at increased risk
of developing coronary heart disease as compared to younger
persons. Another factor to consider is family history. If a person
is the child of parents who developed coronary heart disease before
the age of 55, such offspring are more likely to develop coronary
heart disease themselves than their peers whose parents developed
coronary heart disease after the age 55 or not at all. Lastly,
studies have shown a person's racial or ethnic background can also
be considered a risk factor for developing coronary heart disease,
where African Americans, Mexican Americans, American Indians, and
other Native Americans are at greater risk than Caucasians.
Some coronary risk factors can be controlled. Examples of
controllable coronary risk factors include physical inactivity,
smoking, being overweight or obese, hypertension (high blood
pressure), high blood cholesterol and having diabetes. People with
inactive lifestyles simply have an increased risk of developing
heart disease at some point in their life. In order to reduce this
risk, it is generally advised that a person participate in 30-60
minutes of physical activity on most days. People who smoke
cigarettes have the greatest risk among the general population of
smokers (smoking being a risk factor in and of itself, as it
interferes with the ability of the body to prevent blood clotting),
with those who smoke cigars or pipes having a risk of developing
coronary heart disease that is less than those that smoke
cigarettes. Even if one does not smoke, exposure to other people's
second-hand smoke increases the risk of developing cardiovascular
disease. Naturally then, it follows that quitting smoking helps to
reduce the risk of developing and suffering coronary heart
disease.
Being overweight and/or obese is also a coronary risk factor for
developing coronary heart disease. Persons having too much body fat
are at an increased risk for developing coronary heart disease
and/or eventually experiencing a cardiac event, including instant
death or a nonfatal infarction. In particular, women with waist
measurements of more than 35 inches and men with waist measurements
of more than 40 inches (having too much fat around the waist),
increases that person's risk of developing heart disease. Another
method to measure if a person is at risk is to determine their Body
Mass Index (BMI). A BMI number is a number calculated and based
upon a person's weight and height. For most people, the BMI number
is a reliable indicator of the amount of fat the person carries,
and is typically used by health care professionals to screen for
weight categories that may lead to health problems, such as
diabetes and coronary heart disease. Persons having a BMI value of
25 or greater are considered to be at the highest risk of
developing coronary heart disease.
Hypertension, or high blood pressure, is blood pressure of about
140/90 mmHg or higher. Nearly 1 in 3 American adults has high blood
pressure. Unfortunately, many people that suffer from high blood
pressure are unaware they have elevated pressures until they
experience trouble with their heart, brain, or kidneys. If not
treated, hypertension can lead to heart enlargement, aneurysms in
blood vessels such as at the aorta and arteries in the brain, legs,
and intestines. Furthermore, hypertension can lead to blood vessel
narrowing in the kidney, which may cause a kidney to fail.
Additionally and as stated above, hypertension is one of the many
coronary risk factors, and can lead to hardening of the arteries in
the body, especially those in the heart, brain and kidneys which
can lead to a heart attack, a stroke, or kidney failure.
Having high blood cholesterol and/or high triglyceride levels are
additional coronary risk factors. The term hyperlipidemia means
high lipid levels, and while hyperlipidemia includes several
conditions, it usually means that a patient has high cholesterol
and high triglyceride levels. Persons having total blood
cholesterol level of 200 mg/dL (milligrams/per deciliter) or higher
and/or triglyceride levels above 150 mm/dL have increased risk for
developing coronary heart disease. People that already have other
risk factors and have low-density lipoprotein (LDL) cholesterol
levels of 100 mg/dL or higher are at increased risk also. Persons
with no other risk factors but having low-density lipoprotein (LDL)
levels of 160 mg/dL or higher, and/or with high-density lipoprotein
(HDL) cholesterol levels of less than 40 mg/dL, are also considered
to have an increased risk of developing coronary heart disease.
Commonly prescribed statins (or HMG-CoA reductase inhibitors) are a
class of drugs that are used to lower cholesterol levels in people
with or at risk of cardiovascular disease. Cholesterol is lowered
by inhibition of HMG-CoA reductase, which is the rate-limiting
enzyme of the pathway of cholesterol synthesis, which stimulates
LDL receptors, resulting in an increased clearance of low-density
lipoprotein (LDL) from the bloodstream and a decrease in blood
cholesterol levels. Additionally, maintaining a "heart-healthy"
diet and increased exercise is also advised to patients having high
blood cholesterol and/or high triglyceride levels.
Diabetes is another coronary risk factor. Diabetes mellitus is a
chronic disease in which blood glucose (sugar) levels are too high.
Normal regulation of the hormone, insulin, is responsible for
maintaining proper glucose levels in the blood. Abnormally high
levels of glucose can damage the small and large blood vessels,
leading to diabetic blindness, kidney disease, amputations of
limbs, stroke, and heart disease. Generally, there are two types of
diabetes, Type 1 diabetes is usually (but not always) diagnosed in
children and young adults. The islets of Langerhans, in the
pancreas of people who have type 1 diabetes, do not produce
insulin, and thus such people rely on external insulin, typically
injected subcutaneously or as recently developed inhaled. People
with type 2 diabetes mellitus have insulin resistance, not enough
insulin (low insulin production), or both; they may or may not
eventually require externally supplied insulin to control their
glucose levels and can take oral, systemic medication such as,
metformin (FORTAMET, GLUCOPHAGE, and RIOMET). About 17 million
people in America have Diabetes mellitus, and about 1 million new
cases are diagnosed each year.
Respiratory Disorders
It has been estimated that about 350,000 people in the United
States die from lung disease and that lung disease is the number
three killer in America, responsible for one in seven deaths. About
25 million Americans live with chronic lung disease, which affect
people of all ages and genders.
Bronchitis, asthma and chronic obstructive pulmonary disease (COPD)
are example of some respiratory disorders.
Chronic obstructive pulmonary disease (COPD) is a chronic lung
disease, marked by damage to the lungs and includes two main
illnesses: chronic bronchitis and emphysema, both of which make
breathing difficult. In COPD, the respiratory airways and air sacs
(alveoli) lose their shape, become slack and in some cases, the
walls between sacs are even destroyed. Additionally, excessive
mucus is produced in the airways, as well as the walls of the
airways become inflamed and thickened. As a result, less air gets
in and less air goes out of the lungs. Unfortunately, there is no
cure for COPD.
Cigarette smoking is the most common cause of COPD, and breathing
other kinds of lung irritants such as pollution, dust, or chemical
fumes over a long period of time may also cause or contribute to
COPD.
Bronchitis is an inflammation of the bronchi (medium-size airways)
in the lungs which can be acute (e.g. caused by a virus, bacteria,
dust and fumes) or chronic. In persons with chronic bronchitis, the
bronchial tubes become permanently thickened and/or inflamed. The
patient with chronic bronchitis typically exhibits a persistent,
continuous cough with mucus. A person is diagnosed as having
chronic bronchitis if they cough most days for at least three
months a year in two consecutive years. Smoking, air pollution and
dust or toxic gases can contribute to the chronic bronchitis. In
some instances, chronic inflammation of the airways may lead to
asthma. Typical treatment includes antibiotics (if bacterial),
rest, ingestion of copious amounts of fluids, and over-the-counter
cough medication.
Asthma is typically an allergic disorder of respiration,
characterized by bronchospasm, wheezing, and difficulty in
expiration. It can also be accompanied by coughing and feelings of
chest constriction. Asthma occurs when the main bronchial tubes are
inflamed, resulting in a tightening of the muscles of the bronchial
walls, and can be accompanied by excessive mucus production. As a
result, wheezing up to and including severe difficulty in breathing
can be brought on. In some instances the severity of the
constriction is such that the person experiences an asthma attack,
which can be life-threatening.
The signs of asthma and symptoms can vary from person to person and
from episode to episode and can range from mild to severe.
Occasional asthma episodes with mild, short-lived symptoms such as
wheezing can be experienced wherein between episodes no difficulty
in breathing is experienced. Other asthma sufferers may experience
chronic coughing and wheezing punctuated by severe asthma attacks,
which are typically preceded by warming signs, such as increased
shortness of breath or wheezing, coughing, chest tightness or pain.
In children, an audible whistling or wheezing sound when exhaling
can sometimes be heard, even without a stethoscope (especially
after vigorous activities e.g. running, playing, climbing etc. . .
. ) and frequent coughing spasms.
Medications to treat asthma vary from person to person. In general,
a combination of long-term control medications and quick relief
medications is typically utilized. Medications generally fall into
one of three categories: long-term-control medications,
quick-relief medications and medications for allergy-induced
asthma. Long-term control medications are usually taken every day
on a long-term basis, to control persistent asthma, while quick
relief medications are utilized to relieve symptoms of short-term,
asthma attacks. For allergy-induced asthma, medications are taken
to decrease a person's sensitivity to a particular allergen and
prevent or decrease an immune system reaction to a particular
allergen or allergens.
Exemplary long term medications to treat asthma include inhaled
corticosteroids which are anti-inflammatory drugs that reduce
inflammation in the airways and prevent blood vessels from leaking
fluid into the airway tissues. Exemplary inhaled corticosteroids
include fluticasone (FLOVENT), budesonide (PULMICORT),
triamcinolone (AZMACORT), flunisolide (AEROBID) and beclomethasone
(QVAR). Another long-term medication are the long-acting beta-2
agonists (LABAs), bronchodilators that dialate constricted airways.
Examples include salmeterol (SEREVENT DISKUS) and formoterol
(FORADIL). Still additional long term medications include
leukotriene modifiers, which reduce the production or block the
action of leukotrienes, which are release by cells in the lungs
during an asthma attack. Leukotrienes release results in inflamed
airways, leading to wheezing, mucus overproduction and coughing.
Exemplary leukotriene modifiers include montelukast (SINGLULAIR)
and zafirlukast (ACCOLATE).
Additional long term medications to treat asthma include cromolyn
(INTAL) and nedocromil (TILADE), which require daily inhaled use,
to help prevent attacks of mild to moderate asthma. Theophylline
(dimethylxanthine) requires daily administration, which is a
bronchodilator in pill form.
Quick-relief medications are typically short active bronchodilators
which are designed to address the symptoms of an oncoming or in
progress asthma attack. Examples of quick-relief medications
include short-acting beta-2 agonists, such as albuterol,
prednisone, methylprednisolone and hydrocortisone.
Allergy-desensitization shots (immunotherapy) can also be utilized,
where a series of therapeutic injections containing small doses of
those allergens. These injections are administered once a week for
a few months, then once a month for a period of three to five
years, the theory being that over time, the patient will lose their
sensitivity to the allergens. Additionally, blocking the action of
human immunoglobulin E (IgE), which is commonly involved with
allergies when present in high amounts in the body, is still
another route for treating asthma. Omalizumab (marketed under the
name XOLAIR) is a monoclonal antibody made by Genentech/Novartis
and used mainly in allergy-related asthma therapy, with the purpose
of reducing allergic hypersensitivity. XOLAIR (omalizumab) is a
recombinant DNA-derived humanized IgG1k monoclonal antibody that
selectively binds to human immunoglobulin E (IgE), and limits the
degree of release of mediators of the allergic response, and thus
attenuates the asthmatic response.
Arthritis
Arthritis is a joint disorder that results in inflammation at an
area of a patient where two different bones meet. As such,
arthritis is typically accompanied by joint pain, that can be the
result of wear and tear of cartilage (e.g. osteoarthritis) to pain
associated with inflammation resulting from an overactive immune
system (e.g. rheumatoid arthritis). Arthritis is classified as a
rheumatic disease and as such affects joints, muscles, ligaments,
cartilage, tendons, and may have the potential to affect internal
body organs.
Rheumatoid arthritis (RA) is a long-term disease that causes
inflammation of the joints and surrounding tissues and may affect
other organs/tissues depending on the patient. RA is considered an
autoimmune disease, and it appears to affected women more often
than men. Joints of the extremities (i.e. arms and legs) are most
commonly affected and including but limited to the wrists, fingers,
knees, feet, and ankles.
Symptoms of arthritis include inflammation; pain and limited joint
function e.g., joint stiffness, swelling, redness, and warmth. In
persons suffering RA, symptoms in some patients can include fever,
joint swelling, fatigue, and pain in various organs such as the
lungs, heart, or kidneys.
Various treatment options are typically utilized to treat arthritis
and include NSAIDs (nonsteroidal anti-inflammatory drugs), COX-2
inhibitors, various analgesics and corticosteroids. In some
instances, a physician may choose to directly inject a medicament
into the affected joint. This is known as viscosupplementation, and
involves injection of gel-like substances (hyaluronates) into the
subject a joint to supplement the viscous properties of synovial
fluid in the joint. For example, SYNVISC.RTM. is an FDA-approved
elastic and viscous substance made from hyaluronan that is injected
into the knee to provide pain relief from osteoarthritis.
Clostridial Toxins
The genus Clostridium has more than one hundred and twenty seven
species, grouped according to their morphology and functions. The
anaerobic, gram positive bacterium Clostridium botulinum produces a
potent polypeptide neurotoxin, botulinum toxin, which causes a
neuroparalytic illness in humans and animals referred to as
botulism. The spores of Clostridium botulinum are found in soil and
can grow in improperly sterilized and sealed food containers of
home based canneries, which are the cause of many of the cases of
botulism. The effects of botulism typically appear 18 to 36 hours
after eating the foodstuffs infected with a Clostridium botulinum
culture or spores. The botulinum toxin can apparently pass
unattenuated through the lining of the gut and attack peripheral
motor neurons. Symptoms of botulinum toxin intoxication can
progress from difficulty walking, swallowing, and speaking to
paralysis of the respiratory muscles and death.
About 50 picograms of a commercially available botulinum toxin type
A (a purified neurotoxin complex available from Allergan, Inc., of
Irvine, Calif. under the tradename BOTOX.RTM. in 100 unit vials) is
a LD.sub.50 in mice (i.e. 1 unit). One unit of BOTOX.RTM. contains
about 50 picograms (about 56 attomoles) of botulinum toxin type A
complex. Interestingly, on a molar basis, botulinum toxin type A is
about 1.8 billion times more lethal than diphtheria, about 600
million times more lethal than sodium cyanide, about 30 million
times more lethal than cobra toxin and about 1 2 million times more
lethal than cholera. Singh, Critical Aspects of Bacteria/Protein
Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited by B.
R. Singh et al., Plenum Press, New York (1976) (where the stated
LD.sub.50 of botulinum toxin type A of 0.3 ng equals 1 unit is
corrected for the fact that about 0.05 ng of BOTOX.RTM. equals 1
unit). One unit (U) of botulinum toxin is defined as the LD.sub.50
upon intraperitoneal injection into female Swiss Webster mice
weighing 18 to 20 grams each.
Seven immunologically distinct botulinum neurotoxins have been
characterized, these being respectively botulinum neurotoxin
serotypes A, B, C.sub.1, D, E, F and G, each of which is
distinguished by neutralization with type-specific antibodies. The
different serotypes of botulinum toxin vary in the animal species
that they affect and in the severity and duration of the paralysis
they evoke. For example, it has been determined that botulinum
toxin type A is 500 times more potent, as measured by the rate of
paralysis produced in the rat, than is botulinum toxin type B.
Additionally, botulinum toxin type B has been determined to be
non-toxic in primates at a dose of 480 U/kg which is about 12 times
the primate LD.sub.50 for botulinum toxin type A. Moyer E et al.,
Botulinum Toxin Type 8: Experimental and Clinical Experience, being
chapter 6, pages 71-85 of "Therapy With Botulinum Toxin," edited by
Jankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxin
apparently binds with high affinity to cholinergic motor neurons,
is translocated into the neuron, and blocks the release of
acetylcholine. Additional uptake can take place through low
affinity receptors, as well as by phagocytosis and pinocytosis.
Regardless of stereotype, the molecular mechanism of toxin
intoxication appears to be similar and to involve at least three
steps or stages. In the first step of the process, the toxin binds
to the presynaptic membrane of the target neuron through a specific
interaction between the heavy chain, H chain, and a cell surface
receptor; the receptor is thought to be different for each type of
botulinum toxin and for tetanus toxin. The carboxyl end segment of
the H chain, H.sub.C, appears to be important for targeting of the
toxin to the cell surface. In the second step, the toxin crosses
the plasma membrane of the poisoned cell. The toxin is first
engulfed by the cell through receptor-mediated endocytosis, and an
endosome containing the toxin is formed. The toxin then escapes the
endosome into the cytoplasm of the cell. This step is thought to be
mediated by the amino end segment of the H chain, H.sub.N, which
triggers a conformational change of the toxin in response to a pH
of about 5.5 or lower. Endosomes are known to possess a proton pump
which decreases intra-endosomal pH. The conformational shift
exposes hydrophobic residues in the toxin, which permits the toxin
to embed itself in the endosomal membrane. The toxin (or at a
minimum the light chain) then translocates through the endosomal
membrane into the cytoplasm.
The last step of the mechanism of botulinum toxin activity appears
to involve reduction of the disulfide bond joining the heavy chain,
H chain, and the light chain, L chain. The entire toxic activity of
botulinum and tetanus toxins is contained in the L chain of the
holotoxin; the L chain is a zinc (Zn.sup.2+) endopeptidase which
selectively cleaves proteins essential for recognition and docking
of neurotransmitter-containing vesicles with the cytoplasmic
surface of the plasma membrane, and fusion of the vesicles with the
plasma membrane. Tetanus neurotoxin, botulinum toxin types B, D, F,
and G, cause degradation of synaptobrevin (also called
vesicle-associated membrane protein (VAMP)), a synaptosomal
membrane protein. Most of the VAMP present at the cytoplasmic
surface of the synaptic vesicle is removed as a result of any one
of these cleavage events. Botulinum toxin serotype A and E cleave
SNAP-25. Botulinum toxin serotype C.sub.1 was originally thought to
cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Each
of the botulinum toxins specifically cleaves a different bond,
except botulinum toxin type B (and tetanus toxin) which cleave the
same bond. Each of these cleavages block the process of
vesicle-membrane docking, thereby preventing exocytosis of vesicle
content.
Botulinum toxins have been used in clinical settings for the
treatment of neuromuscular disorders characterized by hyperactive
skeletal muscles (i.e. motor disorders). Almost twenty years ago,
in 1989, a botulinum toxin type A complex was approved by the U.S.
Food and Drug Administration for the treatment of blepharospasm,
strabismus and hemifacial spasm. Subsequently, a botulinum toxin
type A was also approved by the FDA for the treatment of cervical
dystonia and for the treatment of glabellar lines, and a botulinum
toxin type B was approved for the treatment of cervical dystonia.
Non-type A botulinum toxin serotypes apparently have a lower
potency and/or a shorter duration of activity as compared to
botulinum toxin type A. Clinical effects of peripheral
intramuscular botulinum toxin type A are usually seen within one
week of injection. The typical duration of symptomatic relief from
a single intramuscular injection of botulinum toxin type A averages
about three months, although significantly longer periods of
therapeutic activity have been reported.
Although all the botulinum toxin serotypes apparently inhibit
release of the neurotransmitter acetylcholine at the neuromuscular
junction, they do so by affecting different neurosecretory proteins
and/or cleaving these proteins at different sites. For example,
botulinum types A and E both cleave the 25 kiloDalton (kD)
synaptosomal associated protein (SNAP-25), but they target
different amino acid sequences within this protein. Botulinum toxin
types B, D, F and G act on vesicle-associated protein (VAMP, also
called synaptobrevin), with each serotype cleaving the protein at a
different site. Finally, botulinum toxin type C.sub.1 has been
shown to cleave both syntaxin and SNAP-25. These differences in
mechanism of action may affect the relative potency and/or duration
of action of the various botulinum toxin serotypes. Apparently, a
substrate for a botulinum toxin can be found in a variety of
different cell types. See e.g. Biochem J 1; 339 (pt 1):159-65.1999,
and MovDisord, 10(3):376:1995 (pancreatic islet B cells contains at
least SNAP-25 and synaptobrevin).
The molecular weight of the botulinum toxin protein molecule, for
all seven of the known botulinum toxin serotypes, is about 150 kD.
Interestingly, the botulinum toxins are released by Clostridial
bacterium as complexes comprising the 150 kD botulinum toxin
protein molecule along with associated non-toxin proteins. Thus,
the botulinum toxin type A complex can be produced by Clostridial
bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types
B and C.sub.1 are apparently produced as only a 700 kD or 500 kD
complex. Botulinum toxin type D is produced as both 300 kD and 500
kD complexes. Finally, botulinum toxin types E and F are produced
as only approximately 300 kD complexes. The complexes (i.e.
molecular weight greater than about 150 kD) are believed to contain
a non-toxin hemaglutinin protein and a non-toxin and non-toxic
nonhemaglutinin protein. These two non-toxin proteins (which along
with the botulinum toxin molecule comprise the relevant neurotoxin
complex) may act to provide stability against denaturation to the
botulinum toxin molecule, and protection against digestive acids
when toxin is ingested. Additionally, it is possible that the
larger (greater than about 150 kD molecular weight) botulinum toxin
complexes may result in a slower rate of diffusion of the botulinum
toxin away from a site of intramuscular injection of a botulinum
toxin complex.
In vitro studies have indicated that botulinum toxin inhibits
potassium cation induced release of both acetylcholine and
norepinephrine from primary cell cultures of brainstem tissue.
Additionally, it has been reported that botulinum toxin inhibits
the evoked release of both glycine and glutamate in primary
cultures of spinal cord neurons and that in brain synaptosome
preparations botulinum toxin inhibits the release of each of the
neurotransmitters acetylcholine, dopamine, norepinephrine
(Habermann E., et al., Tetanus Toxin and Botulinum A and C
Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain
J Neurochem 51(2); 522-527:1988)), CGRP, substance P, and glutamate
(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate
Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.
Biochem 165; 675-681:1897). Thus, when adequate concentrations are
used, stimulus-evoked release of most neurotransmitters is blocked
by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic
Characterization of Botulinum Toxin For Basic Science and Medicine,
Toxicon 35(9); 1 373-1 412 at 1393; Bigalke H., et al., Botulinum A
Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse
Spinal Cord Neurons in Culture, Brain Research 360; 318-324:1985;
Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the
release of [3H] Noradrenaline and [3H]GABA From Rat Brain
Homogenate, Experientia 44; 224-226: 1988, Bigalke H., et al.,
Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of
Various Transmitters, as Studied with Particulate Preparations From
Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 31
6; 244-251:1 981, and; Jankovic J. et al., Therapy With Botulinum
Toxin, Marcel Dekker, Inc., (1994), page 5.
Botulinum toxin type A can be obtained by establishing and growing
cultures of Clostridium botulinum in a fermenter and then
harvesting and purifying the fermented mixture in accordance with
known procedures. All the botulinum toxin serotypes are initially
synthesized as inactive single chain proteins which must be cleaved
or nicked by proteases to become neuroactive. The bacterial strains
that make botulinum toxin serotypes A and G possess endogenous
proteases and serotypes A and G can therefore be recovered from
bacterial cultures in predominantly their active form. In contrast,
botulinum toxin serotypes C.sub.1, D and E are synthesized by
nonproteolytic strains and are therefore typically unactivated when
recovered from culture. Serotypes B and F are produced by both
proteolytic and nonproteolytic strains and therefore can be
recovered in either the active or inactive form. However, even the
proteolytic strains that produce, for example, the botulinum toxin
type B serotype, only cleave a portion of the toxin produced. The
exact proportion of nicked to unnicked molecules depends on the
length of incubation and the temperature of the culture. Therefore,
a certain percentage of any preparation of, for example, the
botulinum toxin type B toxin, is likely to be inactive, possibly
accounting for the known significantly lower potency of botulinum
toxin type B, as compared to botulinum toxin type A (and thus the
routine use of many thousands of units of botulinum toxin type B,
as known in the art, see e.g. "Long-term safety, efficacy, and
dosing of botulinum toxin type B (MYOBLOC.RTM.) in cervical
dystonia (CD) and other movement disorders" Kumar R and Seeberger L
C. Mov Disord 2002; 17(Suppl 5):S292-S293). The presence of
inactive botulinum toxin molecules in a clinical preparation will
contribute to the overall protein load of the preparation, which
has been linked to increased antigenicity, without contributing to
its clinical efficacy. Additionally, it is known that botulinum
toxin type B has, upon intramuscular injection, a shorter duration
of activity and is also less potent than botulinum toxin type A at
the same dose level.
High quality crystalline botulinum toxin type A can be produced
from the Hall A strain of Clostridium botulinum with
characteristics of >3.times.10.sup.7 U/mg, an
A.sub.260/A.sub.278 of less than 0.60 and a distinct pattern of
banding on gel electrophoresis. The known Schantz process can be
used to obtain crystalline botulinum toxin type A, as set forth in
Schantz, E. J., et al, Properties and use of Botuilnum toxin and
Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56;
80-99:1992. Generally, the botulinum toxin type A complex can be
isolated and purified from an anaerobic fermentation by cultivating
Clostridium botulinum type A in a suitable medium. The known
process can also be used, upon separation out of the non-toxin
proteins, to obtain pure botulinum toxins, such as for example:
purified botulinum toxin type A with an approximately 150 kD
molecular weight with a specific potency of 1-2.times.10.sup.8
LD.sub.50 U/mg or greater; purified botulinum toxin type B with an
approximately 156 kD molecular weight with a specific potency of
1-2.times.10.sup.8 LD.sub.50 U/mg or greater; and purified
botulinum toxin type F with an approximately 155 kD molecular
weight with a specific potency of 1-2.times.10.sup.7 LD.sub.50 U/mg
or greater.
Botulinum toxins and/or botulinum toxin complexes can be obtained
from List Biological Laboratories, Inc., Campbell, Calif.; the
Centre for Applied Microbiology and Research, Porton Down, U.K.;
Wako (Osaka, Japan), Metabiologics (Madison, Wis.) as well as from
Sigma Chemicals of St Louis, Mo. Pure botulinum toxin can also be
used to prepare a pharmaceutical composition for use in accordance
with the present disclosure.
As with enzymes generally, the biological activities of botulinum
toxins (which are intracellular peptidases) is dependant, at least
in part, upon their 3-dimensional conformation. Thus, botulinum
toxin type A is detoxified by heat, various chemicals, surface
stretching, and surface drying. Additionally, it is known that
dilution of the toxin complex obtained by the known culturing,
fermentation and purification to the much lower toxin
concentrations used for pharmaceutical composition formulation
results in rapid detoxification of the toxin unless a suitable
stabilizing agent is present. Dilution of the toxin from milligram
quantities to a solution containing nanograms per milliliter
presents significant difficulties because of the rapid loss of
specific toxicity upon such great dilution. Since the toxin may be
used months or years after the toxin containing pharmaceutical
composition is formulated, the toxin can be stabilized with a
stabilizing agent such as albumin and gelatin.
A commercially available botulinum toxin containing pharmaceutical
composition is sold under the trademark BOTOX.RTM. (available from
Allergan, Inc., of Irvine, Calif.). BOTOX.RTM. consists of a
purified botulinum toxin type A complex, albumin and sodium
chloride packaged in sterile, vacuum-dried form. Botulinum toxin
type A is made from a culture of the Hall strain of Clostridium
botulinum grown in a medium containing N-Z amine and yeast extract.
The botulinum toxin type A complex is purified from the culture
solution by a series of acid precipitations to a crystalline
complex consisting of the active high molecular weight toxin
protein and an associated hemagglutinin protein. The crystalline
complex is re-dissolved in a solution containing saline and albumin
and sterile filtered (0.2 microns) prior to vacuum-drying. The
vacuum-dried product is stored in a freezer at or below -5.degree.
C. BOTOX.RTM. can be reconstituted with sterile, non-preserved
saline prior to intramuscular injection. Each vial of BOTOX.RTM.
contains about 100 U of Clostridium botulinum toxin type A purified
neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9
milligrams of sodium chloride in a sterile, vacuum-dried form
without a preservative.
To reconstitute vacuum-dried BOTOX.RTM., sterile normal saline
without a preservative (0.9% Sodium Chloride Injection) is used by
drawing up the proper amount of diluent in the appropriate size
syringe. Since BOTOX.RTM. may be denatured by bubbling or similar
violent agitation, the diluent is gently injected into the vial.
For sterility reasons BOTOX.RTM. is preferably administered within
four hours after the vial is removed from the freezer and
reconstituted. During these four hours, reconstituted BOTOX.RTM.
can be stored in a refrigerator at about 2.degree. C. to about
8.degree. C. Reconstituted, refrigerated BOTOX.RTM. has been
reported to retain its potency for at least about two weeks
(Neurology, 48:249-53, 1997). It has been reported that botulinum
toxin type A has been used in clinical settings as follows: (1)
about 75-125 U of BOTOX.RTM. per intramuscular injection (multiple
muscles) to treat cervical dystonia; (2) 5-10 U of BOTOX.RTM. per
intramuscular injection to treat glabellar lines (brow furrows) (5
units injected intramuscularly into the procerus muscle and 10
units injected intramuscularly into each corrugator supercilii
muscle); (3) about 30-80 U of BOTOX.RTM. to treat constipation by
intrasphincter injection of the puborectalis muscle; (4) about 1-5
Upper muscle of intramuscularly injected BOTOX.RTM. to treat
blepharospasm by injecting the lateral pre-tarsal orbicularis oculi
muscle of the upper lid and the lateral pre-tarsal orbicularis
oculi of the lower lid; (5) to treat strabismus, extraocular
muscles have been injected intramuscularly with between about 1-5 U
of BOTOX.RTM., the amount injected varying based upon both the size
of the muscle to be injected and the extent of muscle paralysis
desired (i.e. amount of diopter correction desired); (6) to treat
upper limb spasticity following stroke by intramuscular injections
of BOTOX.RTM. into five different upper limb flexor muscles, as
follows: (a) flexor digitorum profundus: 7.5 U to 30 U (b) flexor
digitorum sublimus: 7.5 U to 30 U (c) flexor carpi ulnaris: 10 U to
40 U (d) flexor carpi radialis: 15 U to 60 U (e) biceps brachii: 50
U to 200 U. Each of the five indicated muscles has been injected at
the same treatment session, so that the patient receives from 90 U
to 360 U of upper limb flexor muscle BOTOX.RTM. by intramuscular
injection at each treatment session; (7) to treat migraine,
pericranial (injected symmetrically into glabellar, frontalis and
temporalis muscles) injection of 25 U of BOTOX.RTM. has showed
significant benefit as a prophylactic treatment of migraine
compared to vehicle as measured by decreased measures of migraine
frequency, maximal severity, associated vomiting and acute
medication use over the three month period following the 25 U
injection.
It is known that botulinum toxin type A can have an efficacy for up
to 12 months (European J. Neurology 6 (Supp 4): S11-S1 150: 1999),
and in some circumstances for as long as 27 months, when used to
treat glands, such as in the treatment of hype rhydrosis. See e.g.
Bushara K., Botulinum toxin and rhinorrhea, Otolaryngol Head Neck
Surg 1996; 114(3):507, and The Laryngoscope 109:1344-1346:1999.
However, the usual duration of effect of an intramuscular injection
of BOTOX.RTM. is typically about 3 to 4 months.
The success of botulinum toxin type A to treat a variety of
clinical conditions has led to interest in other botulinum toxin
serotypes. Two commercially available botulinum type A preparations
for use in humans are BOTOX.RTM. available from Allergan, Inc., of
Irvine, Calif., and DYSPORT.RTM. available from Beaufour Ipsen,
Porton Down, England. A botulinum toxin type B preparation
(MYOBLOC.RTM.) is available from Solstice Pharmaceuticals of San
Francisco, Calif.
A botulinum toxin has also been proposed for or has been used to
treat otitis media of the ear (U.S. Pat. No. 5,766,605), inner ear
disorders (U.S. Pat. Nos. 6,265,379; 6,358,926), tension headache,
(U.S. Pat. No. 6,458,365), migraine headache pain (U.S. Pat. No.
5,714,468), post-operative pain and visceral pain (U.S. Pat. No.
6,464,986), hair growth and hair retention (U.S. Pat. No.
6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484),
injured muscles (U.S. Pat. No. 6,423,319) various cancers (U.S.
Pat. Nos. 6,139,845), smooth muscle disorders (U.S. Pat. No.
5,437,291), and neurogenic inflammation (U.S. Pat. No. 6,063,768).
Controlled release toxin implants are known (see e.g. U.S. Pat.
Nos. 6,306,423 and 6,312,708) as is transdermal botulinum toxin
administration (U.S. patent application Ser. No. 10/194,805). U.S.
Patent Application Publication 2007/0048334 A1, Ser. No. 11/211,311
and filed Aug. 24, 2005, discloses the use of a botulinum toxin to
improve gastric emptying and/or treating gastroesophageal reflux
disease (GERD) by administration to a patient's head, neck and
shoulder muscles. It is known that a botulinum toxin can be used to
weaken the chewing or biting muscle of the mouth so that self
inflicted wounds and resulting ulcers can heal (Payne M., et al,
Botulinum toxin as a novel treatment for self mutilation in
Lesch-Nyhan syndrome, Ann Neurol 2002 September; 52(3 Supp
1):S157).). U.S. Patent Application Publication 20050191321 A1,
Ser. No. 11/039,506 and filed Jan. 18, 2004, discloses treating
medication overuse disorders (MOD), by local administration of a
Clostridial toxin. U.S. Patent Application Publication 20050147626
A1, Ser. No. 10/964,898 and filed Oct. 12, 2004 discloses treating
or preventing, by peripheral administration of a botulinum toxin to
or to the vicinity of a trigeminal sensory nerve, a neurological
disorder and/or a neuropsychiatric disorder.
Additionally, a botulinum toxin may have an effect to reduce
induced inflammatory pain in a rat formalin model. Aoki K., et al,
Mechanisms of the antinociceptive effect of subcutaneous
BOTOX.RTM.: Inhibition of peripheral and central nociceptive
processing, Cephalalgia 2003 September; 23(7):649. Furthermore, it
has been reported that botulinum toxin nerve blockage can cause a
reduction of epidermal thickness. Li Y, et al., Sensory and motor
denervation influences epidermal thickness in rat foot glabrous
skin, Exp Neurol 1997; 147:452-462 (see page 459). U.S. Patent
Application Publication 20050266029 A1, Ser. No. 11/159569 and
filed on Jun. 22, 2005 relates to methods for treating pain
associated with arthritis. Finally, it is known to administer a
botulinum toxin to the foot to treat excessive foot sweating
(Katsambas A., et al., Cutaneous diseases of the foot: Unapproved
treatments, Clin Dermatol 2002 November-December; 20(6):689-699;
Sevim, S., et al., Botulinum toxin-A therapy for palmar and plantar
hyperhidrosis, Acta Neurol Belg 2002 December; 102(4):167-70),
spastic toes (Suputtitada, A., Local botulinum toxin type A
injections in the treatment of spastic toes, Am J Phys Med Rehabil
2002 October; 81(10):770-5), idiopathic toe walking (Tacks, L., et
al., Idiopathic toe walking: Treatment with botulinum toxin A
injection, Dev Med Child Neurol 2002; 44(Suppl 91):6), and foot
dystonia (Rogers J., et al., Injections of botulinum toxin A in
foot dystonia, Neurology 1993 April; 43(4 Suppl 2)). Tetanus toxin,
as wells as derivatives (i.e. with a non-native targeting moiety),
fragments, hybrids and chimeras thereof can also have therapeutic
utility. The tetanus toxin bears many similarities to the botulinum
toxins. Thus, both the tetanus toxin and the botulinum toxins are
polypeptides made by closely related species of Clostridium
(Clostridium tetani and Clostridium botulinum, respectively).
Additionally, both the tetanus toxin and the botulinum toxins are
dichain proteins composed of a light chain (molecular weight about
50 kD) covalently bound by a single disulfide bond to a heavy chain
(molecular weight about 100 kD). Hence, the molecular weight of
tetanus toxin and of each of the seven botulinum toxins
(non-complexed) is about 150 kD. Furthermore, for both the tetanus
toxin and the botulinum toxins, the light chain bears the domain
which exhibits intracellular biological (protease) activity, while
the heavy chain comprises the receptor binding (immunogenic) and
cell membrane translocational domains.
Additionally, both the tetanus toxin and the botulinum toxins
exhibit a high, specific affinity for gangliocide receptors on the
surface of presynaptic cholinergic neurons. Receptor mediated
endocytosis of tetanus toxin by peripheral cholinergic neurons
results in retrograde axonal transport, blocking of the release of
inhibitory neurotransmitters from central synapses and a spastic
paralysis. Contrarily, receptor mediated endocytosis of botulinum
toxin by peripheral cholinergic neurons results in little if any
retrograde transport, inhibition of acetylcholine exocytosis from
the intoxicated peripheral motor neurons and a flaccid
paralysis.
Finally, the tetanus toxin and the botulinum toxins resemble each
other in both biosynthesis and molecular architecture. Thus, there
is an overall 34% identity between the protein sequences of tetanus
toxin and botulinum toxin type A, and a sequence identity as high
as 62% for some functional domains. Binz T. et al., The Complete
Sequence of Botulinum Neurotoxin Type A and Comparison with Other
Clostridial Neurotoxins, J Biological Chemistry 265(16);
9153-9158:1990.
Acetylcholine
Typically only a single type of small molecule neurotransmitter is
released by each type of neuron in the mammalian nervous system.
The neurotransmitter acetylcholine is secreted by neurons in many
areas of the brain, but specifically by the large pyramidal cells
of the motor cortex, by several different neurons in the basal
ganglia, by the motor neurons that innervate the skeletal muscles,
by the preganglionic neurons of the autonomic nervous system (both
sympathetic and parasympathetic), by the postganglionic neurons of
the parasympathetic nervous system, and by some of the
postganglionic neurons of the sympathetic nervous system.
Essentially, only the postganglionic sympathetic nerve fibers to
the sweat glands, the piloerector muscles and a few blood vessels
are cholinergic as most of the postganglionic neurons of the
sympathetic nervous system secret the neurotransmitter
norepinephine. In most instances acetylcholine has an excitatory
effect. However, acetylcholine is known to have inhibitory effects
at some of the peripheral parasympathetic nerve endings, such as
inhibition of heart rate by the vagal nerve.
The efferent signals of the autonomic nervous system are
transmitted to the body through either the sympathetic nervous
system or the parasympathetic nervous system. The preganglionic
neurons of the sympathetic nervous system extend from preganglionic
sympathetic neuron cell bodies located in the intermediolateral
horn of the spinal cord. The preganglionic sympathetic nerve
fibers, extending from the cell body, synapse with postganglionic
neurons located in either a paravertebral sympathetic ganglion or
in a prevertebral ganglion. Since, the preganglionic neurons of
both the sympathetic and parasympathetic nervous system are
cholinergic, application of acetylcholine to the ganglia will
excite both sympathetic and parasympathetic postganglionic
neurons.
Acetylcholine activates two types of receptors, muscarinic and
nicotinic receptors. The muscarinic receptors are found in all
effector cells stimulated by the postganglionic neurons of the
parasympathetic nervous system, as well as in those stimulated by
the postganglionic cholinergic neurons of the sympathetic nervous
system. The nicotinic receptors are found in the synapses between
the preganglionic and postganglionic neurons of both the
sympathetic and parasympathetic. The nicotinic receptors are also
present in many membranes of skeletal muscle fibers at the
neuromuscular junction.
Acetylcholine is released from cholinergic neurons when small,
clear, intracellular vesicles fuse with the presynaptic neuronal
cell membrane. A wide variety of non-neuronal secretory cells, such
as, adrenal medulla (as well as the PC12 cell line) and pancreatic
islet cells release catecholamines and parathyroid hormone,
respectively, from large dense-core vesicles. The PC12 cell line is
a clone of rat pheochromocytoma cells extensively used as a tissue
culture model for studies of sympathoadrenal development. Botulinum
toxin inhibits the release of both types of compounds from both
types of cells in vitro, permeabilized (as by electroporation) or
by direct injection of the toxin into the denervated cell.
Botulinum toxin is also known to block release of the
neurotransmitter glutamate from cortical synaptosomes cell
cultures.
What is needed therefore are effective and efficient methods for
treating arthritis, respiratory disorders, such as COPD, asthma,
bronchitis and for treating/alleviating (e.g. lowering) coronary
risk factors, such as hypertension, high cholesterol, high
triglyceride levels, diabetes, hyperlipidemia, and obesity that do
not require daily administration and/or strict patient
compliance.
SUMMARY
The present invention meets this need and provides methods for
treating a respiratory disorder and/or arthritis or and/or coronary
risk factor by intramuscular, subcutaneous or intradermal
administration of a botulinum toxin to at least one of a head or
neck and shoulder location of a patient in need thereof, that is, a
patient with a respiratory disorder and/or arthritis and/or a
coronary risk factor. Intracranial administration of a botulinum
neurotoxin, that is, administration within the cranium and into
brain tissue, is specifically excluded from the scope of the
present invention.
According to one aspect of the present invention, the botulinum
toxin is one of the botulinum toxin types A, B, C.sub.1, D, E, F
and G and is preferably botulinum toxin type A. The botulinum toxin
(as a complex or as a pure, about 150 kDa protein) can be
formulated with the excipient (such as an albumin) in an amount of
between about 1 unit and about 25,000 units of the botulinum toxin.
Preferably, the quantity of the botulinum toxin administered is
between about 5 units and about 1500 units of a botulinum toxin
type A. Where the botulinum toxin is botulinum toxin type B,
preferably, the quantity of the botulinum toxin associated with the
carrier can be between about 250 units and about 25,000 units of a
botulinum toxin type B.
The amount of a botulinum toxin administered within the scope of
the present invention during a given period can be between about
10.sup.-3 U/kg and about 35 U/kg per patient weight for a botulinum
toxin type A and up to about 1500 U/kg per patient weight for other
botulinum toxins, such as a botulinum toxin type B.
Preferably, the amount of a type A botulinum toxin administered is
between about 10.sup.-2 U/kg and about 25 U/kg. Preferably, the
amount of a type B botulinum toxin administered during a given
period is between about 10.sup.-2 U/kg and about 1000 U/kg. More
preferably, the type A botulinum toxin is administered in an amount
of between about 10.sup.-1 U/kg and about 15 U/kg. Most preferably,
the type A botulinum toxin is administered in an amount of between
about 1 U/kg and about 10 U/kg. In many instances, administration
of from about 1 unit to about 500 units of a botulinum toxin type A
can provide effective and long lasting therapeutic relief. More
preferably, from about 5 units to about 300 units of a botulinum
toxin, such as a botulinum toxin type A, can be used and most
preferably, from about 10 units to about 200 units of a neurotoxin,
such as a botulinum toxin type A, can be locally administered into
a target tissue with efficacious results. In a particularly
preferred embodiment of the present invention, from about 20 units
to about 300 units of a botulinum toxin, such as botulinum toxin
type A, can be administered with therapeutically effective
results.
The botulinum toxin can be made by Clostridium botulinum.
Additionally, the botulinum toxin can be a modified botulinum
toxin, that is, a botulinum toxin that has at least one of its
amino acids deleted, modified or replaced, as compared to the
native or wild type botulinum toxin. Furthermore, the botulinum
toxin can be a recombinant produced botulinum toxin or a derivative
or fragment thereof.
A method herein disclosed can be carried out by administration of a
botulinum toxin to a patient in need thereof, i.e., having a
coronary risk factor and/or arthritis and/or a respiratory disorder
to be treated. Notably, the botulinum toxin is administered to a
head, neck or shoulder location of a patient to provide a
therapeutic effect upon the arthritis, coronary risk factor or
respiratory disorder. Thus, the botulinum toxin is not administered
so as to provide a therapeutic effect at the local site of
administration of the botulinum toxin. Quiet the contrary i.e.
administration of a botulinum toxin (as by intramuscular
administration) to a head, neck or shoulder location (e.g. to an
intramuscular site to one or more of the well known frontalis
muscle, glabellar muscle, occipitalis muscle, temporalis muscle,
masseter muscle, trapezius muscle, semispinalis muscle and splenius
capitis muscles, and/or subcutaneously or intradermally at or in
the vicinity of these muscles) has a therapeutic effect, as
determined by alleviation of at least one symptom associated with
arthritis, coronary risk factor or a respiratory disorder.
The botulinum toxin (as either a complex or as a pure [i.e. about
150 kDa molecule] can be a botulinum toxin A, B, C, D, E, F or G.
Administration of the botulinum toxin in accordance with the
instant disclosure can be by a transdermal route (i.e. by
application of a botulinum toxin in a cream, patch or lotion
vehicle), subdermal route (i.e. subcutaneous or intramuscular), or
intradermal route of administration to at least one of a patient's
head, neck or shoulder.
A hypothesized physiological reason for the efficacy of my
invention is that the head, neck and/or administration of a
botulinum toxin according to my invention reduces, inhibits and/or
eliminates sensory input (afferent) from peripheral location(s) of
the head and/or neck and/or shoulder into the central nervous
system (including to the brain) which input kindles, generates,
exacerbates and/or facilitates development, worsening or
maintenance of a coronary risk factor, arthritis, or a respiratory
disorder in a patient.
A particular dose of a botulinum used in a particular patient
according to the present invention is typically less than the
amount of a botulinum toxin that would be used to paralyze (i.e.
result in complete loss of function or tone of a muscle) a muscle,
since an intent of a method according to the present invention is
not to paralyze a muscle but to reduce a sensory output from
sensory neurons located in or on a muscle, or in or under the skin.
As medicaments are typically utilized in the art, botulinum
neurotoxin is administered to a particular patient at a starting
amount, after which the patient is follow up with and any
beneficial effect is noted. If no change and no adverse effect to
the administered toxin is observed, the attending medical
profession may choose to increase the dose of toxin administered
and/or alter the location(s) of administration of the toxin.
The present invention encompasses a method for treating arthritis,
a coronary risk factor or a respiratory disorder by administering a
botulinum toxin to a head and/or neck and/or shoulder location of a
patient with arthritis and/or coronary risk factor and/or a
respiratory disorder, thereby treating the arthritis, coronary risk
factor or a respiratory disorder. The botulinum toxin can be a
botulinum toxins types A, B, C.sub.1, D, E, F or G. Most
preferably, the botulinum toxin is a botulinum toxin type A. The
botulinum toxin administered can be a botulinum toxin complex (i.e.
from about 300 kDa to about 900 kDa in molecular weight) or a pure
botulinum toxin, that is, the about 150 kDa neurotoxic component of
a botulinum toxin complex.
The coronary risk factor to be treated can be hypertension,
diabetes, hyperlipidemia, and obesity, for example. The respiratory
disorder treated can be, for example, asthma, bronchitis and
chronic obstructive pulmonary disease.
Administration of a botulinum toxin according to the method
disclosed herein can be by intramuscular or subdermal
administration of the botulinum toxin to a head and/or neck and/or
shoulder muscle of the patient. In some embodiments the patient can
have a coronary risk factor and/or a respiratory disorder and/or
arthritis as well as a headache, such as a tension headache,
migraine (episodic or chronic), hormonal headache, cluster
headache, sinus headache and cervogenic headache. A patient is said
to suffer from chronic migraine headache when experiencing a
migraine headache for fifteen days or greater per month, while a
patient that suffers between 0 to eight days of migraine headaches
per month is considered to suffer from episodic migraines.
In one aspect, a method for treating a respiratory disorder in a
patient in need thereof comprises the step of administering a
botulinum toxin to at least one of a head, neck or shoulder
location of the patient with a respiratory disorder to thereby
alleviate at least one symptom of the respiratory disorder and
treat the respiratory disorder. In a particular embodiment, the
administration step is carried out by intramuscular administration
of the botulinum toxin to a muscle at the at least one of the head,
neck or shoulder location of the patient.
Exemplary coronary risk factors that can be alleviated and treated
in accordance with the instant disclosure include hypertension,
diabetes, hyperlipidemia and obesity, for example.
In some embodiments the botulinum toxin is a botulinum toxin type A
or B and is administered to a muscle selected from the group
consisting of a frontalis muscle, a glabellar muscle, an
occipitalis muscle, a temporalis muscle, a masseter muscle, a
trapezius muscle, a semispinalis muscle and a splenius capitis
muscle. The locations of all of these muscles are well known to
those of ordinary skill in the art, and can easily be found in any
of several medical anatomy texts, for example.
In still other embodiments, a method for treating arthritis in a
patient in need thereof comprises the step of intramuscular
administration of a therapeutically effective amount of a botulinum
neurotoxin, such as toxin type A or a botulinum toxin type B, to at
least one muscle selected from the group consisting of a frontalis
muscle, glabellar muscle, occipitalis muscle, temporalis muscle,
masseter muscle, trapezius muscle, semispinalis muscle and splenius
capitis muscle of a patient with arthritis. The patient can also
suffer from headaches, such as chronic or episodic migraines. In
some examples, the botulinum toxin administered is from about 5 to
about 2500 units of a botulinum toxin type A or from about 100 to
about 25,000 units of a botulinum toxin type B. An exemplary
administered amount of botulinum neurotoxin can be from about 5
units to about 2500 units, depending upon factors such as the
botulinum neurotoxin serotype used, the mass of the patient treated
and the severity of the patient's condition, of course.
In one detailed embodiment of a method for treating a respiratory
disorder and/or coronary risk factor and/or arthritis in a patient,
according to the present invention, intramuscular administration of
a therapeutically effective amount of a botulinum toxin type A to
each of the frontalis, glabellar, occipitalis, temporalis,
masseter, trapezium, semispinalis and splenius capitis muscles of a
patient in need thereof, that is, with arthritis, a respiratory
disorder and/or coronary risk factor, thereby treating the
arthritis and/or respiratory disorder and/or coronary risk factor
of the patient.
In still other aspects, the present invention provides for
treatment of an arthritis pain in a patient in need thereof
comprising the step of intramuscular administration of a
therapeutically effective amount of a botulinum toxin type A or a
botulinum toxin type B to at least two muscles selected from the
group consisting of a frontalis muscle, glabellar muscle,
occipitalis muscle, temporalis muscle, masseter muscle, trapezius
muscle, semispinalis muscle and splenius capitis muscle of the
patient. In particular embodiments, the patient experiences
arthritis pain located at joint of an extremity (i.e. an arm of
leg), for example, such as a wrist joint, finger joint, elbow
joint, toe joint, ankle joint, hip joints and knee joint, shoulder
joint. In some embodiments, the botulinum toxin administered is
from about 5 to about 2500 units of a botulinum toxin type A or
from about 100 to about 25,000 units of a botulinum toxin type B.
Additionally, the patient may also suffer a headache, such as a
tension headache, a migraine headache, an episodic migraine, a
chronic migraine, a cluster headache, a sinus headache, a chronic
progressive headache, a hormone headache and a cervogenic headache.
In particular instances, the migraine headache can be a chronic
migraine or episodic migraine.
DEFINITIONS
The following definitions apply herein.
"About" means plus or minus ten percent of the value so
qualified.
"Biocompatible" means that there is an insignificant inflammatory
or immunogenic response from use of a botulinum toxin according to
the present invention.
"Biologically active compound" means a compound which can effect a
beneficial change in the subject to which it is administered. For
example, "biologically active compounds" include neurotoxins.
"Therapeutically effective amount" as applied to the biologically
active compound (such as a botulinum toxin) means that amount of
the compound which is generally sufficient to effect a desired
change in a patient. For example, where the desired effect is
treatment of a coronary risk factor and/or a respiratory disorder,
an effective amount of the compound is that amount which causes an
alleviation of the a coronary risk factor and/or a respiratory
disorder, as observed clinically, without a significant systemic
toxicity resulting.
"Neurotoxin" means an agent which can interrupt nerve impulse
transmission across a neuromuscular or neuroglandular junction,
block or reduce neuronal exocytosis of a neurotransmitter or alter
the action potential at a sodium channel voltage gate of a
neuron.
"Treatment" or "treating" means any treatment of a disease in a
mammal, and includes: (i) preventing the disease from occurring or;
(ii) inhibiting the disease, i.e., arresting its development; (iii)
relieving the disease, i.e., reducing the incidence or severity
(i.e. alleviation) of symptoms of or causing regression of the
disease, such as, for example, by a reduction in blood pressure,
reduction in number and/or severity of asthma attacks, a reduction
in a need for, or elimination of, a medication associated with a
respiratory disorder or coronary risk factor, reduced blood
cholesterol or triglyceride levels, for example. Treating or
alleviation of at least one symptom associated with arthritis, a
coronary risk factor or respiratory disorder is considered to be
treating the particular arthritis, coronary risk factor and/or
respiratory disorder suffered by the patient in need of the
treatment.
Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention
DESCRIPTION
The present invention is based upon a method for treating arthritis
and/or a coronary risk factor and/or a respiratory disorder by
local administration of a botulinum neurotoxin to a head, neck or
shoulder location of a patient with a coronary risk factor and/or a
respiratory disorder. Thus and in particular, treatment is
preferably by intramuscular injection of a botulinum neurotoxin to
a head, neck or shoulder location of the patient. Most preferably,
botulinum neurotoxin type A is utilized, permitting delivery of
long-lasting therapeutic amounts of a bioactive botulinum toxin to
treat the arthritis and/or coronary risk factor and/or respiratory
disorder. After administration of the botulinum neurotoxin in
accordance with the teachings of the present invention, at least
one symptom of at least one of a coronary risk factor or symptom of
a respiratory disorder and/or arthritis are alleviated.
Administration of a botulinum neurotoxin can be used to treat a
coronary risk factor, arthritis pain and respiratory disorders is
surprising because of the apparent lack of systemic connection or
control/biofeedback mechanisms between the head, neck and/or
shoulder location to which the botulinum toxin is administered and
the at least one coronary risk factor and/or respiratory disorder
and/or arthritis pain to be treated. Additionally, in some
instances, patients in need of treatment of their coronary risk
factor and/or arthritis pain and/or respiratory disorder(s) can
also have a headache, such as a tension headache, a migraine
headache, an episodic migraine, a chronic migraine, a cluster
headache, a sinus headache, a chronic progressive headache, a
hormone headache and a cervogenic headache.
Additionally, whereas the botulinum neurotoxin is to be
administered at a head, neck or shoulder location, at least one
arthritis symptoms is alleviated at distal joint location(s), such
as a finger joint, a toe joint, an ankle joint, an elbow joint, a
knee joint, a wrist joint and a hip joint for example.
The therapeutic dose of administered botulinum toxin is such that
there are nominal or insignificant systemic effects due to any
botulinum neurotoxin which passes into the circulatory system.
Preferably, the botulinum to neurotoxin used to practice a method
within the scope of the present invention is one of the serotype A,
B, C.sub.1, D, E, F or G botulinum neurotoxins. Preferably, the
botulinum neurotoxin used is botulinum toxin type A, because of its
high potency in humans, ready availability, and known safe and
efficacious use for treatment of various disorders for over two
decades.
The present invention includes within its scope the use of any
botulinum neurotoxin which has a therapeutic effect to treat
arthritis or coronary risk factor or respiratory disorder according
to the present invention (i.e. administered to a head neck or
shoulder location). For example, neurotoxins made by any of the
species of the toxin producing Clostridium bacteria, such as
Clostridium botulinum, Clostridium butyricum, and Clostridium
beratti can be used or adapted for use in the methods of the
present invention. Additionally, all of the botulinum serotypes A,
B, C.sub.1, D, E, F and G can be advantageously used in the
practice of the present invention, although type A is the most
preferred serotype, as explained above.
The present invention includes within its scope: (a) a botulinum
neurotoxin complex as well as a pure botulinum neurotoxin obtained
or processed by bacterial culturing, toxin extraction,
concentration, preservation, freeze drying and/or reconstitution
and; (b) modified or recombinant botulinum neurotoxin, that is
botulinum neurotoxin that has had one or more amino acids or amino
acid sequences deliberately deleted, modified or replaced by known
chemical/biochemical amino acid modification procedures or by use
of known host cell/recombinant vector recombinant technologies, as
well as derivatives or fragments of botulinum neurotoxins so made,
and includes botulinum neurotoxins with one or more attached
targeting moieties for a cell surface receptor present on a
cell.
Botulinum toxins for use according to the present invention can be
stored in lyophilized or vacuum dried form in containers under
vacuum pressure. Prior to lyophilization, the botulinum toxin can
be combined with pharmaceutically acceptable excipients,
stabilizers and/or carriers, such as albumin. The lyophilized or
vacuum dried material can be reconstituted with saline or water in
accordance with known methods of reconstitution. Additionally, the
botulinum toxin for use in accordance with the method herein
disclosed can be provided as ready-to-use injectable solutions from
their manufacturer. For example, Myobloc.RTM. (Botulinum Toxin Type
B) is provided as an injectable solution in vials containing 5000
units of botulinum toxin type B per mL in 0.05% human serum
albumin, 0.01 M sodium succinate, 0.1 M sodium chloride at
approximately pH 5.6.
Methods for determining the appropriate dosage is generally
determined on a case by case basis by the attending physician. Such
determinations are routine to one of ordinary skill in the art (see
for example, Harrison's Principles of Internal Medicine (1998),
edited by Anthony Fauci et al., 14.sup.th edition, and published by
McGraw Hill). Appropriate dosage administration of botulinum toxin,
and modification thereof, is a feature of administration that one
of ordinary skill in the art is familiar. Exemplary dosages are
provided below to guide the practitioner. However and in accordance
with common medical practice, dosages may be increased or
decreased, according to the particular outcome/results observed
after a particular botulinum neurotoxin is administered to a
particular patient at a particular location.
For example, Table 1 provides a medical practitioner with a guide
to exemplary amounts of administration (location and units) of a
botulinum toxin type A (BOTOX.RTM.) to a patient:
TABLE-US-00001 TABLE 1 Muscle Area Number of Units Bilateral
Injection Total Dose (U) Frontalis/ About 25 to No About 25 to
about Glabellar about 40 40 Occipitalis About 10 Yes 20 Temporalis
About 10 to Yes About 20 to about about 25 50 Masseter About 0 to
about Yes About 0 to about (optional) 25 50 Trapezius About 10 to
Yes About 20 to about about 30 60 Semispinalis About 5 to about Yes
About 10 to about 10 20 Splenius capitis About 5 to about Yes About
10 to 10 about 20 Total Dose About 105 to Range about 260
BOTOX.RTM. is available from Allergan, Irvine, Calif., and each
vial contains 100 U of Clostridium botulinum toxin type A, 0.5 mg
albumin (human), and 0.9 mg sodium chloride in a sterile,
vacuum-dried form without a preservative. One U corresponds to the
calculated median lethal intraperitoneal dose (LD.sub.50) in mice.
The vials are stored in a freezer between -20 degrees Centigrade
and -5.degree Centigrade before use. Toxin can be administered to
only one of the muscles of Table 1 or at least two or more, as best
seen fit by the medical practitioner. Note, as set forth in the
table above, as little as 5 units of BOTOX.RTM. can be administered
if only one muscle is injected with the botulinum toxin. The units
listed above are of BOTOX.RTM., but different serotypes or strains
of a botulinum toxin can be used, and different amounts may be
administered. For example, about 3-4 times of DYSPORT.RTM. (a
botulinum toxin type A) may be utilized (i.e. up to about 1040
units), and about 40-50 times of NEUROBLOC.RTM./MYOBLOC.RTM. may be
utilized (i.e. up to about 13,000 units) relative to BOTOX.RTM.
units, to achieve a desired therapeutic effect, respectively.
EXAMPLES
The following examples set forth specific compositions and methods
encompassed by the present invention and are not intended to limit
the scope of the present invention.
Example 1
Method for Treating Asthma
A 20 year old male presents with wheezing, shortness of breath and
coughing. He states that he coughs and wheezes practically every
day for about 6 hours per day, the coughing and wheezing being
exacerbated when he exerts himself playing tennis or basketball. On
occasion he reports that he sometimes experiences tightness of the
chest, which ends his games early. After a review of the patient's
symptoms, medical history, and physical examination, his physician
conducts a pulmonary (lung) function test, utilizing a spirometer.
The physician determines that the patient suffers from asthma, and
he is provided with an inhalable short-acting medication,
inhaled/metered albuterol (.beta.2-adrenergic receptor agonist), to
inhale when his chest tightening and coughing is exacerbated. After
1-month, the patient returns to his physician to report the inhaler
is not effective, and that he continually misplaces it, which does
not allow him to inhale the albuterol when he needs it most.
The patient is therefore treated by administration of a botulinum
neurotoxin into one or more head, neck and shoulder muscles, for
example, by intramuscular administration. In particular, a
botulinum toxin type A (BOTOX.RTM.) is administered in the
following pattern and amounts. Intramuscularly and utilizing a
26-gauge needle, about 5 units of botulinum toxin type A is
symmetrically and bilaterally injected at two sites, separated by 1
cm, into each of the occipitalis muscles (4 total injections into
the occipitalis muscles, for about 20 units), 5 units is
symmetrically and bilaterally injected at four sites in the
frontalis muscle (2 injection sites at about 0.5 inch above the
eyebrows and vertical to the medial canthus, and 2 injection sites,
each 1 inch laterally and upward to the hairline in a "V"
configuration from the first two injections, for a total of 20
units into the frontalis muscle), and 1 injection of 5 units into
approximately the center of each of the temporalis muscles (total
of 10 units into the temporalis muscles) for a total of about 50
units of botulinum toxin.
At a follow up one month later, the patient reports that within 7
days of botulinum toxin administration he wheezes less than 1.5
hours/day and that he can participate in and complete a whole game
of tennis. An in-office measurement of lung function shows
improvement of forced vital capacity (amount of air exhaled with
force after inhalation as deeply as possible) as well as forced
expiratory volume (amount of air you can exhale with force in one
breath, measured at 1 second (FEV1), 2 seconds (FEV2), or 3 seconds
(FEV3).
Example 2
Method for Treating Bronchitis
A 39 year old female presents with a rough cough that produces
copious amounts of mucus. Additionally, the patient complains of
shortness of breath, fatigue, swelling of her feet and ankles and
has blue-tinged lips as a result of low levels of oxygen, and is
running a low grade fever of about 38.5 degrees Celsius. The
patient has had these symptoms for over two months, and after
conducting a pulmonary function test (PFT) and high resolution
computed tomography (HRCT) to observe her lungs, and her physician
notes she has a heavy mucus buildup in her bronchi. The patient is
treated with bronchodilator medications and instructed to get at
least nine hours of sleep per day. The patent returns after two
months, reporting no alleviation of her symptoms. The doctor
determines that she is suffering from bronchitis and decides to
administer a botulinum toxin to her temporalis, trapezius and
frontalis muscles.
Taking an imaginary vertical line down the midline and front of the
patient's forehead, the forehead is imagined to be divided into two
halves. Three injections of 10 units each of botulinum toxin type A
(DYSPORT.RTM.) are made laterally and midway between the hairline
and eyebrows, to the left from this imaginary midline and towards
the patients temple, evenly spaced apart about 1.5 cm. The same is
done to the right, for a total of six injections into the frontalis
muscle (60 units of DYSPORT.RTM. into the forehead). Additionally,
one injection of 20 units is administered into each of the two
temporalis muscles (40 units total of DYSPORT.RTM. to temporalis
muscles), and 50 units is administered into each of the trapezius
muscles (100 units total of DYSPORT.RTM. into the trapezius
muscles). Within 3 days, the patient reports that the swelling of
her feet and ankles has decreased and she no longer coughs when
breathing and no longer has blue-tinged lips. Additionally, the
symptoms of her bronchitis remain alleviated for approximately 3
months.
Example 3
Method for Treating COPD
A 57 year old chain-smoking man presets with a hacking, chronic
cough. He informs his doctor that he has smoked since he was 10
years old and has several very bad colds each winter for the last
few years. He further informs the doctor that he has the most
difficulty breathing in the morning and evening. The patient finds
that short walks result in breathlessness and walking up the stairs
in front of his house is difficult. After a thorough physical exam,
the doctor determines that patient has both chronic bronchitis and
emphysema (COPD), which are obstructing his airflow (in and out of
his lungs), thus interfering with normal breathing.
The patient is treated by administering from about 100 to 200 units
of a botulinum toxin type A (BOTOX.RTM.) (or from 4000 to about
8000 units of a botulinum toxin type B (MYOBLOC.RTM.). Into each of
his trapezius muscles, 20 units of botulinum toxin type A is
administered (total of 40 units bilaterally) and 10 units is
administered to each of the semispinalis dorsi, semispinalis
cervicis semispinalis capitis (total of 60 units bilaterally).
Within 10 days after this administration protocol, the patient's
breathlessness and walking up stairs is alleviated, and coughs only
in the early morning.
Example 4
Method for Treating Hypertension and Obesity
A 43 year old partner at a successful advertising agency complains
to his doctor that he hears ringing in his ears and is suffering
dizzy spells at least once a day. The doctor notes that his 5 foot
6 inch, 302 pound patient appears to sweat continuously and appears
to be under a great amount of stress. Taking his blood pressure, it
is noted that it reads 202/120 mmHg. Despite previous prescriptions
of 2-[4-[2-hydroxy-3-(1-methylethylamino)propoxy]phenyl]ethanamide,
a .beta.1 receptor specific antagonist (trade name Tenormin), his
patient's hypertension is unaffected. The doctor administers about
10 units of a botulinum toxin type A (BOTOX.RTM.) to each of the
muscles listed in Table 1 (for a total of about 140 units). During
a follow up visit two weeks later, the patient's blood pressure is
taken again, this time reading at 155/90 mmHg, a positive
alleviation of the hypertension. It is also noted that the patient
has lost approximately 6 pounds since his last weigh in. The
patient also reports that since administration of the botulinum
toxin, he no longer experiences ringing in his ears and has only
been dizzy only once since his last visit.
The doctor follows up with the patient a month later, and notes
that his blood pressure now reads at 142/87 mmHg and the patient
weights 6 pounds less. It is determined that the patient be
administered a regime of botulinum toxin, as administered to him in
the first instance, every 4.5 months. As a result and within one
year, the patient loses 53 pounds and has an average blood pressure
of 136/78 mmHg.
Example 5
Method for Treating Diabetes
A 64 year old woman, 5 feet, 2 inches tall and weighing 187 pounds,
presents to her doctor, complaining of headaches, blurred vision
and an insatiable thirst. Her physician determines her fasting
blood glucose level after an overnight fast (not eating anything
after midnight). The patient registers a value of 152 mg/dl the
first time her blood glucose level is measured, and 163 mg/dl a
week later. It is determined, after conducting an oral glucose
tolerance test performed in the doctor's office, that the patient
is diabetic (oral glucose tolerance tests shows that her blood
glucose level at 2 hours is equal to or more than 223 mg/dl).
She is administered 200 units of a botulinum toxin type B (e.g.
MYOBLOC.RTM.) intramuscularly into each of her temporalis muscles
on each side of her head, at points approximately 1 inch from the
top of her earlobe and towards the head's apex (two injections for
a total of 400 units of a botulinum toxin type B into the
temporalis muscles), and 200 units bilaterally and about one inch
above the top of her eyebrow arches, into the frontalis (two
injections for a total of 400 units of a botulinum toxin type B in
the frontalis) and 100 units into each of two injections into
glabellar muscle, utilizing her glabellar lines as guides (two
injections for a total of 200 units of botulinum toxin type B), for
a grand total of 1000 units of botulinum toxin type B. Within eight
days, the patient reports that her thirst has lessened and no
longer experiences headaches. At the doctor's office 2 months
later, an oral glucose tolerance test reveals that the patient has
impaired glucose tolerance (i.e., a 2-hour glucose result from an
oral glucose tolerance test registering 145 mg/dl) instead of
diabetes, which is lower that when first measured (223 mg/dl).
Example 5
Method for Treating Hyperlipidemia
A 26 year old male presents with a total blood cholesterol level of
370 mg/dL, an LDL cholesterol level of 210 mg/dL and an HDL level
of 32 mg/dL. Although the patient exercises regularly
(3.times./week for 1 hour each time) and takes a statin prescribed
by his doctor to lower his LDL levels, his lipid profile does not
improve. H is physician decides that the patient will be
administered a botulinum toxin type A (BOTOX.RTM.), where about 20
units evenly divide among 4 injection points are intramuscularly
administered into his glabellar lines, and about 50 units into each
of his temporalis muscles (for a total of 100 units into the
temporalis muscles), and about 50 units into each of his trapezius
muscles (about 100 units into the trapezius muscles), for a total
administration of about 220 units of botulinum toxin type A.
After 1 month, the patient returns and his cholesterol levels are
lower, now having a total blood cholesterol level of 260 mg/dL and
his LDL cholesterol level is 162 mg/dL and HDL level is 40 mg/dL.
After one year, the doctor notes that the patient's total blood
cholesterol level is now 210 mg/dL and his LDL cholesterol level is
110 mg/dL and has an HDL level of 42 mg/dL.
Example 6
Method for Treating Arthritis
A 57 year old mechanic reports to his doctor that pain due to the
arthritis in his hands and fingers is becoming unbearable, and
rates his pain at a 9 on the visual analogue scale for pain (VAS)
at the doctor's office. Application of various topical creams that
contain ingredients such as methyl salicylate, menthol and
capsaicin are simply ineffective. The physician decides to
administer a botulinum toxin type A in order to treat the arthritis
to the patient's trapezius, frontalis and occipitalis muscles.
The doctor administers a total of 100 units of a botulinum toxin
type A (BOTOX.RTM.) as follows: about 50 units into the frontalis
muscle (five injections of about 10 units each across the forehead
of the patient (along an approximately horizontal midline between
the eyebrows and hairline of the patient) and 40 units into the
trapezius muscles (two injections/10 units each into the left and
two injections/10 units each into the right trapezius, for a total
of 40 units into the trapezius muscles) and 10 units into the
occipitalis muscles (two injections/5 units each). After about 8
days, the patient reports that his arthritic pain is alleviated and
ranks his pain at only a 2 on the same VAS. The arthritic pain
remains alleviated for about at least about 3 months.
Example 7
Method for Treating Arthritis
A 39 year old female long distance runner (and known osteoarthritis
sufferer) complains to her family doctor that her knee joints ache
most of the time, and that her running regimen is being hampered by
the pain, rating as an 8 on the doctor's visual analogue scale for
pain (VAS). After prescribing NSAIDs for 2 months, the patient
reports that no improvement or alleviation of the pain.
Accordingly, the doctor decides to treat the arthritis pain by
administration of a botulinum toxin into the splenius capitis and
temporalis muscles. About 50 units of a botulinum toxin type A
(DYSPORT.RTM.) is bilaterally injected, i.e. about 25 units into
the left and right splenius capitis muscles, and 100 units is
bilaterally injected, i.e. 50 units into each of her temporalis
muscles.
After 10 days, the patient reports returns to the doctor's office
for a follow up and reports that the pain in her knees is
alleviated, and now when asked to rate her pain on the visual
analogue scale for pain (VAS), she rates it as a 3, a good and
desirable improvement. The patient is similarly administered the
botulinum toxin every 6 months thereafter.
Compositions and methods according to the invention disclosed
herein have many advantages, including that a botulinum toxin can
be used to provide therapeutically effective treatment of coronary
risk factors, a respiratory disorder and arthritis.
All references, articles, publications and patents and patent
applications cited herein are incorporated by reference in their
entireties.
Although the present invention has been described in detail with
regard to certain preferred methods, other embodiments, versions,
and modifications within the scope of the present invention are
possible. For example, a wide variety of neurotoxins can be
effectively used in the methods of the present invention.
Additionally, the present invention includes formulations wherein
two or more neurotoxins, such as two or more botulinum toxins, are
administered concurrently or consecutively. For example, botulinum
toxin type A can be administered until a loss of clinical response
or neutralizing antibodies develop, followed by administration of a
botulinum toxin type B or E. Alternately, a combination of any two
or more of the botulinum serotypes A-G can be locally administered
to control the onset and duration of the desired therapeutic
result.
Furthermore, non-neurotoxin compounds can be administered prior to,
concurrently with or subsequent to administration of the neurotoxin
formulation so as to provide an adjunct effect such as enhanced or
a more rapid onset of denervation before the neurotoxin, such as a
botulinum toxin, begins to exert its therapeutic effect.
The present invention also includes within its scope the use of a
neurotoxin, such as a botulinum toxin, in the preparation of a
medicament for use to treat a treating coronary risk factor and/or
respiratory disorders and/or arthritis by administration of the
botulinum toxin to a head, neck and/or shoulder location of a
patient with a coronary risk factor and/or respiratory disorder
and/or arthritis.
Accordingly, the spirit and scope of the following claims should
not be limited to the descriptions of the preferred embodiments set
forth above.
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